EA036289B1 - Fused tricyclic imidazo pyrazines as modulators of tnf activity - Google Patents

Abstract

The invention relates to substituted fused tricyclic imidazo pyrazine derivatives and analogues thereof, represented by formula (I)being potent modulators of human TNF activity, and are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders.

Description

The present invention relates to a class of condensed imidazole derivatives and their use in therapy. More specifically, the present invention relates to pharmacologically active substituted fused tricyclic imidazopyrazine derivatives and analogs thereof.

These compounds are modulators of TNFa signaling and are therefore useful as pharmaceuticals, especially for the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders and cancer disorders. ...

TNFa is a prototypical member of the superfamily of tumor necrosis factor (TNF) proteins, which share a common primary function, regulating cell viability and cell death. One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to and activate specific receptors of the TNF superfamily. For example, TNFa exists in soluble and transmembrane forms and transmits a signal through two receptors known as TNFR1 and TNFR2 to different functional endpoints.

Various products are already commercially available to modulate TNFa activity. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn's disease. All currently approved products are macromolecular and act by inhibiting the binding of human TNFa to its receptor. Typical macromolecular TNFa inhibitors include anti-TNFa antibodies and soluble TNFa receptor fusion proteins. Examples of commercially available antibodies to TNFa include complete human antibodies such as adalimumab (gumira®) and golimumab (simpony®), chimeric antibodies such as infliximab (remicade®), and pegylated Fab 'fragments such as certolizumabpegol (cymsia®) ... An example of a commercially available soluble TNFα receptor fusion protein is etanercept (Enbrel®).

Members of the TNF superfamily, including TNFa itself, are involved in a variety of physiological and pathological functions that are thought to play a role in a number of pathological conditions of importance in medicine (see, for example, MG Tansey & DE Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088 and FS Carneiro et al., J. Sexual Medicine, 2010, 7, 3823-3834).

Therefore, the compounds of the present invention, which are active modulators of human TNFa activity, are useful for the treatment and / or prevention of various human diseases. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ophthalmic disorders; and oncological disorders

In addition, the compounds of the present invention may be useful as pharmacological standards in the development of new biological tests and in the search for new pharmacological agents. Thus, in one embodiment, the compounds of the present invention can be used as radioligands in assays designed to detect pharmacologically active compounds. In an alternative embodiment, some of the compounds of the present invention can be used to couple to a fluorophore to produce fluorescent conjugates that can be used in assays (eg, fluorescence polarization studies) to detect pharmacologically active compounds.

In the applications for international patents WO 2013/186229, WO 2014/009295 and WO 2014/009296 condensed derivatives of imidazole are described, which are modulators of human TNFa activity.

International patent applications WO 2015/086525 and WO 2015/086526 published on June 18, 2015 describe fused tricyclic imidazole derivatives which are modulators of TNFa signaling.

However, none of the presently available prior art documents discloses or proposes exactly the structural class of fused tricyclic imidazopyrazine derivatives as proposed in the present invention.

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

- 1 036289 n denotes an integer equal to 0 or 1;

Y is phenyl, which may optionally have one or more substituents selected from halogen and difluoromethoxy;

X is oxygen or a linear or branched C ₁ -C ₄ alkylene chain;

R ¹ is halogen or heteroaryl, which may optionally have one or more substituents selected from hydroxy, hydroxy (C ₁ -C ₆ ) alkyl and C ₁ -C ₆ alkoxy;

R ² and R ³ independently represent hydrogen;

R ⁴ is hydrogen;

R ^5a is hydrogen, hydroxy or —OR ^a ;

R ^5b is hydrogen;

R ^a denotes C ₁ -C ₆ ^ km, which may optionally contain one or more substituents selected from C ₁ -C6-alkoxy, oxo and aminocarbonyl; and where heteroaryl means monovalent aromatic groups of at least 5 atoms formed from one ring or multiple fused rings in which one or more carbon atoms are replaced by one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

The present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in therapy.

The present invention also relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of disorders for which administration of a TNFα inhibitor is indicated.

Another object of the present invention is the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of an inflammatory or autoimmune disorder.

Another aspect of the present invention is a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of an inflammatory or autoimmune disorder.

The compounds of the invention may be used in a method of treating and / or preventing disorders for which administration of a modulator of TNFa function is indicated, which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof in an effective amount.

The compounds of the invention can be used in a method of treating and / or preventing an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof in an effective amount.

If any group contained in the compounds of formula (I) above is indicated to be optionally substituted, that group may be unsubstituted or have one or more substituents. Typically, such groups are unsubstituted or contain one or two substituents.

For use in medicine, the salts of the compounds of formula (I) must be pharmaceutically acceptable salts. However, other salts may be used to prepare compounds useful in the present invention or pharmaceutically acceptable salts thereof. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in the publication Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.

Suitable pharmaceutically acceptable salts of compounds useful in the present invention include acid addition salts, which, for example, can be prepared by mixing a solution of a compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, or phosphoric acid. In addition, if the compounds useful in the present invention contain an acidic moiety, such as a carboxy group, then suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, eg, quaternary ammonium salts, and meglumine salts.

The scope of the present invention includes solvates of the compounds of formula (I) above. Such solvates can be prepared with conventional organic solvents, for example hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; simple ether solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) can be prepared with water, in which case they will be hydrates.

Co-crystals are also within the scope of the present invention. The technical term co-crystal is used to describe the case where the neutral molecular components are contained in the crystalline compound at a certain stoichiometric ratio. The preparation of pharmaceutical co-crystals allows the crystalline form of an active pharmaceutical ingredient to be modified, which in turn can alter its physicochemical characteristics without impairing its required biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012). Typical examples of co-crystal forming substances that may be contained in the co-crystal with the active pharmaceutical ingredient include L-ascorbic acid, citric acid, glutaric acid, urea, and nicotinamide.

Within the scope of the present invention are prodrugs of the compounds of formula (I) above. Typically such prodrugs are functional derivatives of formula (I) that are readily convertible in vivo to the desired compound of formula (I). Conventional techniques for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Suitable alkyl groups that may be contained in the compounds useful in the present invention include straight and branched chain Cl-C ₆ alkyl groups, for example Ci-C-i-alkyl groups. Typical examples include methyl and ethyl groups, and straight or branched chain propyl, butyl and pentyl groups. Preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2,2-dimethylpropyl, and 3-methylbutyl. Derived expressions such as C1-Sa-alkoxy, _C1-C6 alkylthio, _C1-C6 alkylsulfonyl and _C1-C6 alkylamino, are formed appropriately.

The expression C ₁ -C ₄ -alkylene chain means a bivalent linear or branched alkylene chain containing from 1 to 4 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene, and dimethylmethylene.

Suitable C ₂ -C ₆ alkenyl groups include vinyl and allyl.

Suitable C ₂ -C ₆ alkynyl groups include ethynyl, propargyl and butynyl.

The term C ₃ -C ₇ -cycloalkyl as used in the present invention means monovalent groups of 3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon and may include benzene-fused analogs thereof. Suitable C3-C7 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, and cycloheptyl.

The term C ₄ -C ₇ -cycloalkenyl as used in the present invention means monovalent groups of 4 to 7 carbon atoms derived from a partially unsaturated monocyclic hydrocarbon. Suitable C ₄ -C ₇ cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

The term C ₄ -C ₉ -bicycloalkyl as used herein means monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical C ₄ -C ₉ bicycloalkyl groups include bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.2] octanyl, and bicyclo [3.3.1] nonanyl.

Typical (C ₄ -C ₉ ) bicycloalkenyl groups include bicyclo [3.1.0] hexenyl.

The term aryl as used in the present invention means monovalent carbocyclic aromatic groups formed from one aromatic ring or multiple fused aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl _(C1-C6) alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

The term C ₃ -C ₇ -heterocycloalkyl as used in the present invention means saturated monocyclic rings containing from 3 to 7 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and may include condensed with benzene ring analogs. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, dihydroisoindolyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro [1,2,5] thiadiazolo [2,3-a] pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinil, thiomorpholinil, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl, azocanyl, (imino) (oxo) thiazinanyl, (oxo) thiazinanyl, and (dioxo) thiazinanyl.

The term C ₃ -C ₇ heterocycloalkenyl as used herein means mono- 3 036289 unsaturated or polyunsaturated monocyclic rings containing from 3 to 7 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and may include their benzene-fused analogs. Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl, and 1,2,3,6tetrahydropyridinyl.

The term C ₄ -C ₉ -heterobicycloalkyl as used herein means C ₄ -C ₉ bicycloalkyl as defined in the present invention, in which one or more carbon atoms are replaced by one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Typical heterobicycloalkyl groups include 3-azabicyclo [3.1.0] hexanyl, 2-oxa-5-azabicyclo [2.2.1] heptanyl, 6-azabicyclo [3.2.0] heptanyl, 3-azabicyclo [3.1.1] heptanyl, 3- azabicyclo [4.1.0] -heptanyl, 2-oxabicyclo [2.2.2] octanyl, quinuclidinyl, 2-oxa-5azabicyclo [2.2.2] octanyl, 3-azabicyclo [3.2.1] octanyl, 8-azabicyclo [3.2. 1] octanyl, 3-oxa-8-azabicyclo [3.2.1] octanyl, 3,8-diazabicyclo [3.2.1] octanyl, 3,6-diazabicyclo- [3.2.2] nonanyl, 3-oxa-7-azabicyclo [3.3.1] nonanyl and 3,9-diazabicyclo [4.2.1] -nonanyl.

The term C ₄ -C ₉ -spiroheterocycloalkyl as used in the present invention means saturated bicyclic ring systems containing from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, in which two rings are connected by a common atom. Typical spiroheterocycloalkyl groups include 5-azaspiro [2.3] hexanyl, 5-azaspiro- [2.4] heptanyl, 2-azaspiro [3.3] heptanyl, 2-oxa-6-azaspiro [3.3] heptanyl, 2-oxa-6-azaspiro [ 3.4] octanyl, 2-oxa-6-azaspiro [3.5] nonanyl, 7-oxa-2-azaspiro [3.5] nonanyl, 2-oxa-7azaspiro [3.5] nonanyl, and 2,4,8-triazaspiro [4.5] decanyl.

The term heteroaryl as used in the present invention means monovalent aromatic groups containing at least 5 atoms formed from one ring or a plurality of fused rings in which one or more carbon atoms are replaced by one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno [2,3-c] pyrazolyl, thieno [3,4-b] [1,4] dioxynyl, dibenzothienyl, pyrrolyl, indolyl, 2,3-dihydro -1H-isoindolyl, pyrrolo [2,3-b] pyridinyl, pyrrolo [3,2-c] pyridinyl, pyrrolo [3.4-b | pyridinyl. pyrazolyl, pyrazolo [1,5-a] pyridinyl, pyrazolo [3,4 ^] pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imothiazolidazole [2,1-b] thiazolyl, imidazo [1,2-a] pyridinyl, imidazo [4,5-b] pyridinyl, purinyl, imidazo [1,2-a] pyrimidinyl, imidazo [1,2-a] pyrazinyl, oxadiazolyl , thiadiazolyl, triazolyl, [1,2,4] triazolo [1,5-a] pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl triazinyl and chromenyl groups.

The term halogen as used in the present invention includes atoms of fluorine, chlorine, bromine and iodine, usually fluorine, chlorine or bromine.

If the compounds of formula (I) contain one or more asymmetric centers, they can exist as the corresponding enantiomers. If the compounds to be used in the present invention contain two or more asymmetric centers, they can also exist as diastereoisomers. It should be understood that the present invention includes the use of all such enantiomers and diastereoisomers and mixtures thereof in any ratio, including racemates.

Formula (I) and the formulas below in the present invention include all individual stereoisomers and all possible mixtures thereof, unless otherwise indicated or represented. In addition, compounds of formula (I) can exist as tautomers, for example, ketone tautomers (C'H ₂ C. '= O) -oenol (CH = CHOH) or amide tautomers (HHC-O) ^ hydroxyimine (N = COH ). Formula (I) and the formulas below in the present invention include all individual tautomers and all possible mixtures thereof, unless otherwise indicated or indicated.

An illustrative example of a tautomer of the present invention is 2-oxo (1H) -pyridinyl, which is the tautomer of 2-hydroxypyridinyl.

It should be understood that each individual atom contained in formula (I), or in the formulas below in the present invention, may in fact be contained in the form of any of its naturally occurring isotopes, with the most commonly occurring isotope (s) being preferred. ... For example, each single hydrogen atom contained in the formula (I), either in the formulas shown hereinafter, may be present in the form of atom 1 H, ² H (deuterium) and ³ H (tritium), preferably in the form of 1H. Likewise, for example, each individual carbon atom contained in formula (I) or in the formulas below in the present invention may be contained as ¹² C, ¹³ C or ¹⁴ C, preferably ¹² C ...

In one embodiment, n is an integer equal to 0. In another embodiment, n is an integer equal to 1.

In a preferred embodiment, n is an integer equal to 1.

Typically X is oxygen or a linear or branched C ₁ -C ₄ alkylene chain.

In the first embodiment, X is oxygen.

In a second embodiment, X is a straight or branched C ₁ -C ₄ alkylene chain. In this embodiment, typical values for X include methylene (-CH ₂ -), (methyl) methylene, ethylene (-CH2CH2-), (ethyl) methylene, (dimethyl) methylene, (methyl) ethylene, propylene (-CH2CH2CH2-), (propyl) methylene and (dimethyl) ethylene. Preferred X values include methylene and oxygen.

In a preferred embodiment, X is oxygen. In another preferred embodiment, X is methylene.

It is preferred if Y is phenyl, which may optionally have one or more substituents.

Examples of optional substituents that may be present on the Y moiety include 1, 2, or 3 substituents independently selected from the group consisting of halogen, difluoromethoxy.

Examples of preferred substituents on the Y moiety include fluoro, chloro, bromo, difluoromethoxy.

Typical examples of specific substituents on the Y moiety include chloro, fluoro difluoromethoxy.

Typical values for Y include phenyl, fluorophenyl (including 2-fluorophenyl, 3-fluorophenyl, and 4fluorophenyl), chlorophenyl (including 2-chlorophenyl, 3-chlorophenyl, and 4-chlorophenyl), difluorophenyl (including 2,6difluorophenyl), (chloro) (fluoro) phenyl (including 5-chloro-2-fluorophenyl and 2-chloro-5-fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyl and 2,6-dichlorophenyl), (difluoromethoxy) phenyl [including 2- (difluoromethoxy) phenyl, 3 - (difluoromethoxy) phenyl and 4- (difluoromethoxy) phenyl], (bis- (difluoromethoxy)) phenyl [including 2,5 (bis- (difluoromethoxy)) phenyl and including 2,6- (bis- (difluoromethoxy)) phenyl] , (difluoromethoxy) (fluoro) phenyl [including 2- (difluoromethoxy) -5-fluorophenyl, 2- (difluoromethoxy) -3-fluorophenyl, 2- (difluoromethoxy) -4fluorophenyl, 2- (difluoromethoxy) -5-fluorophenyl, 2- (difluoromethoxy) -6-fluorophenyl and 5- (difluoromethoxy) -2fluorophenyl], (difluoromethoxy) (difluoro) phenyl [including 2-difluoromethoxy-3,5-difluorophenyl and difluoromethoxy-3,5-difluorophenyl)], (chlorine) ( difluoromethoxy) phenyl [including 2-chloro-5- (difluoromethoxy) phenyl, 5-chloro-2- (difluoromethoxy) phenyl, 5-chloro-3- (difluoromethoxy) phenyl and 6-chloro-2- (di fluoromethoxy) phenyl].

Selected Y values include phenyl, (chloro) (fluoro) phenyl, dichlorophenyl, (difluoromethoxy) phenyl, (bis- (difluoromethoxy)) phenyl, (difluoromethoxy) (fluoro) phenyl, (difluoromethoxy) - (difluoro) phenyl, (chlorine) (difluoromethoxy) phenyl, (chloro) (trifluoromethoxy) phenyl.

Preferred values for Y include (difluoromethoxy) phenyl, (difluoromethoxy) (fluoro) phenyl, and (chloro) (difluoromethoxy) phenyl.

Specific values for Y include 2-difluoromethoxy-phenyl, 2-difluoromethoxy-5-chlorophenyl, 2-difluoromethoxy-5-chlorophenyl, and 2-difluoromethoxy-5-fluorophenyl.

In a preferred embodiment, Y is 2- (difluoromethoxy) phenyl.

In another preferred embodiment, Y is 2- (difluoromethoxy) -5 chlorophenyl.

Usually R ¹ denotes halogen, heteroaryl, where any of these groups may optionally have one or more substituents.

Typically R ² and R ^{3 are} independently hydrogen.

Typically R ⁴ is hydrogen.

Preferably R ^5a is hydrogen, hydroxy or —OR ^a and R ^5b is hydrogen.

In a first embodiment, R ¹ is halogen. In one embodiment of this embodiment, R ¹ is bromine. In a second embodiment, R ¹ is chlorine.

In a second embodiment, R ¹ is optionally substituted heteroaryl. In some embodiments of this embodiment, R ¹ is benzofuryl, thienyl, indolyl, isoindolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, where any of these groups may optionally have one or more substituents.

Preferably, if R ¹ is chlorine, bromine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, where any of these groups may optionally have one or more substituents.

For example, R ¹ is bromine; or pyridinyl or (morpholino) -pyrimidinyl, where any of these groups may optionally have one or more substituents.

Typical examples of optional substituents for R ¹ include 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, hydroxyCC-CD alkyl, C ₁ -C ₆ alkoxy group.

- 5 036289

Typical examples of preferred substituents for R ¹ include 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy.

Selected examples of substituents for R ¹ include 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy.

Illustrative examples of substituents for R ¹ include 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, hydroxyisopropyl, methoxy.

In a preferred embodiment, R ^{1 is} substituted with hydroxyCC ^ -Oalkyl. In one embodiment of this embodiment, R ^{1 is} substituted with hydroxyisopropyl, preferably 2hydroxyprop-2-yl.

In a second preferred embodiment, R ^{1 is} substituted with C ₁ -C ₆ alkoxy. In one embodiment of this embodiment, R ^{1 is} substituted with a methoxy group.

In a third preferred embodiment, R ^{1 is} substituted with hydroxy.

Typical R ¹ values include bromine, chlorine, methoxy-azetidinyl, methoxypyrrolidinyl, (methoxymethyl) pyrrolidinyl, morpholinyl, benzofuryl, thienyl, indolyl, pyrazolyl, hydroxyisopropylthiazolyl, pyridinyl, hydroxyisopropyl-pyridinyl, hydroxy-pyridinyl, hydroxy-pyridinyl, hydroxy-di-pyridinyl methoxypyrimidinyl, hydroxypyrazinyl, hydroxyisopropylpyrazinyl, hydroxymethylpyrimidinyl, hydroxycyclobutylpyrimidinyl.

Illustrative values for R ¹ include bromine, (methoxy) pyridinyl. Illustrative values for R ¹ further include hydroxyisopropylpyridinyl, preferably 2-hydroxyprop-2-ylpyridinyl.

Typically R ² is hydrogen.

Typically R ³ is hydrogen.

Typically R ⁴ is hydrogen.

Typically R ^5a is hydrogen, hydroxy or —OR ^a .

In a first embodiment, R ^5a is hydrogen. In a second embodiment, R ^5a is hydroxy. In a third embodiment, R ^5a is —OR ^a . In one embodiment of this embodiment, R ^a is optionally substituted C ₁ -C ₆ alkyl. In a selected embodiment, R ^5a is hydrogen, hydroxy, or —OR ^a .

In a preferred embodiment, R ^5a is hydrogen.

Typically R ^5b is hydrogen.

Typical examples of suitable substituents for R ^a include C ₁ -C ₆ alkoxy, oxo, aminocarbonyl.

Typical examples of specific substituents for R ^a include methoxy, isopropoxy, oxo, aminocarbonyl.

Selected values for R ^a include methyl, ethyl, where any of these groups may optionally have one or more substituents.

Selected examples of suitable substituents for R ^a include C ₁ -C ₆ alkoxy and oxo. Additional examples of suitable substituents for R ^a include aminocarbonyl.

Selected examples of specific substituents for R ^a include methoxy and oxo. Additional selected examples of suitable substituents for R ^a include aminocarbonyl. In one embodiment, R ^a is optionally substituted C1-C6 alkyl. In one embodiment of this embodiment, in the ideal case R ^a represents unsubstituted _C1-C6 alkyl, preferably methyl. In another embodiment of this embodiment, R ^a is ideally substituted C ₁ -C ₆ alkyl, preferably methyl. Particular values for R ^a include methyl, methoxyethyl.

Selected values for R ^5a include hydrogen, hydroxy, methoxy, and (aminocarbonyl) methyloxy. Selected values for R ^5b include hydrogen.

Illustrative values for R ^5a include hydrogen, hydroxy, and (aminocarbonyl) methyloxy.

Preferred R ^5b values include hydrogen.

In a preferred embodiment, R ^5a is as defined above and R ^5b is hydrogen. In a preferred embodiment of this embodiment, R ^5a is hydroxy.

In another preferred embodiment, R ^5a and R ^{5b are} independently hydrogen.

In yet another embodiment, R ^5a is (aminocarbonyl) methyloxy and R ^5b is hydrogen.

One subclass of compounds of formula (I) according to the present invention is represented by compounds of formula (IIA) and their pharmaceutically acceptable salts:

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wherein

R ¹ , R ^5a , R ^5b , X and Y are as defined above. A preferred subgroup of compounds of formula (IIA) is represented by compounds of formula (IIA-A) and their pharmaceutically acceptable salts:

wherein

R ⁶ and R ⁷ independently represent hydrogen, halogen, difluoromethoxy and

X, R ¹ , R ^5a and R ^5b are as defined above.

Typically, R ⁶ and R ⁷ can independently be hydrogen, fluoro, chloro, bromo, difluoromethoxy.

Typical values for R ⁶ include hydrogen, halogen, difluoromethoxy.

In a first embodiment, R ⁶ is hydrogen. In a second embodiment, R ⁶ is halogen. In a first embodiment of this embodiment, R ⁶ is fluorine. In a second embodiment of this embodiment, R ⁶ is chlorine. In a third embodiment, R ⁶ is difluoromethoxy. Selected values for R ⁶ include hydrogen, fluorine, chlorine, difluoromethoxy.

For example, R ⁶ is a difluoromethoxy group.

Typical values for R ⁷ include hydrogen, halogen, difluoromethoxy.

In a first embodiment, R ⁷ is hydrogen. In a second embodiment, R ⁷ is halogen. In a first embodiment of this embodiment, R ⁷ is fluorine. In a second embodiment of this embodiment, R ⁷ is chlorine. In a third embodiment, R ⁷ is difluoromethoxy. Selected values for R ⁷ include hydrogen, fluorine, chlorine, difluoromethoxy.

For example, R ⁷ is hydrogen.

In a preferred embodiment, R ^{7 is} attached to the phenyl ring at the para position relative to the R ⁶ moiety.

In another embodiment, R ⁶ and R ^{7 are} attached to the phenyl ring at positions 2 and 6.

In yet another embodiment, R ⁶ and R ^{7 are} attached to the phenyl ring at positions 2 and 5.

A preferred subgroup of compounds of formula (IIA-A) above are those of formula (IIA-AB) and pharmaceutically acceptable salts thereof:

wherein

V is CR ¹¹ or N;

R ⁸ is hydrogen, hydroxy, hydroxy _(C1-C6) alkyl, _C1-C6 alkoxy;

R ⁹ and R ¹⁰ independently represent hydrogen;

R ¹¹ is hydrogen and

X, R ^a , R ^b , R ^c , R ^5a , R ^5b , R ⁶ and R ⁷ are as defined above.

In one embodiment, V is CR ¹¹ . In another embodiment, V is N.

Typically R ⁸ is (hydroxy ^ C ^ C ^ alkyl, C ^ C ^ alkoxy.

In a first embodiment, R ⁸ is (hydroxy ^ C ^ C ^ alkyl. In one embodiment of this embodiment, R ⁸ is (hydroxy) isopropyl.

In a second embodiment, R ⁸ is hydroxy. In a third embodiment R ⁸ is C1-C ₆ -alkoxy. In one embodiment of this embodiment, R ⁸ is methoxy.

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Preferably, when R ⁸ is hydroxy, _C1-C6 alkoxy, (hydroxy) _-C1-C6 alkyl.

For example, R ⁸ is hydroxy, C ₁ -C ₆ alkoxy. For example, R ⁸ additionally denotes (hydroxy ^ C ^^ - alkyl.

Selected values for R ⁸ include hydrogen, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy.

Usually R ⁸ denotes hydrogen, hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy.

Preferably R ⁸ is hydroxy, methoxy, hydroxyisopropyl.

For example, R ⁸ is hydroxy, methoxy. For example, R ^{8 is} additionally hydroxyisopropyl.

In one embodiment, R ⁹ is hydrogen. In one embodiment, R ¹⁰ is hydrogen. In a preferred embodiment, R ⁹ and R ^{10 are} independently hydrogen.

Typically R ¹¹ is hydrogen.

In a preferred embodiment, R ¹¹ is hydrogen.

Another subclass of compounds of formula (I) according to the present invention is represented by compounds of formula (IIB) and their pharmaceutically acceptable salts

γ (IV) in which

R ¹ , R ^5a , R ^5b , X and Y are as defined above. A preferred subgroup of compounds of formula (IIB) is represented by compounds of formula (IIB-A) and pharmaceutically acceptable salts thereof

(PV-A) in which X, R ¹ , R ^5a , R ^5b , R ⁶ and R ⁷ are as defined above.

A preferred subgroup of compounds of formula (IIA-A) above are those of formula (IIA-AB) and pharmaceutically acceptable salts thereof

(PV-AB) in which X, R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above.

Specific new compounds proposed in the present invention include all compounds, the preparation of which is described in the accompanying examples, and their pharmaceutically acceptable salts and solvates, and their joint crystals.

Therefore, a preferred object of the present invention are compounds of formula (I), which are selected from the group consisting of

1- [2- (difluoromethoxy) phenyl] -8- (6-methoxypyridin-3-yl) -3,4-dihydro-1Hpyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine ;

1- [2- (difluoromethoxy) phenyl] -8- [2- (morpholin-4-yl) pyrimidin-5-yl] -3,4 dihydro- 1H-pyrano [4 ', 3': 4.5] imidazo [ 1,2-a] pyrazine;

5- {1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazin-8-yl} pyridine- 2 (1H) -one;

- 8 036289 (18) -8-bromo-1 - [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine;

(1K) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine;

(18) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine;

(1K) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine;

(6K, 8K) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) 3-pyridyl] -7,8-dihydro-6H-cyclopenta [ 1,2] imidazo [3,4-b] pyrazin-6-ol;

(68,88) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) 3-pyridyl] -7,8-dihydro-6H-cyclopenta [ 1,2] imidazo [3,4-b] pyrazin-6-ol;

2 - [[(6K, 8K) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1methylethyl) -3-pyridyl] -7,8-dihydro-6H -cyclopenta [1,2] imidazo [3,4-b] pyrazin6-yl] oxy] acetamide; and

2 - [[(68.88) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1methylethyl) -3-pyridyl] -7,8-dihydro-6H -cyclopenta [1,2] imidazo [3,4-b] pyrazin6-yl] oxy] acetamide.

The compounds of the present invention are useful for the treatment and / or prevention of various human diseases. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ophthalmic disorders; and oncological disorders.

Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders, and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, polymyositis, scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile arthritis and juvenile arthritis polyarticular types), chronic anemia (ACD), Still's disease (occurring in adolescence and / or adults), Behcet's disease, and Sjogren's syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison's disease, hemolytic or malignant anemia, acute kidney injury (AKI; including cisplatin-induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy) (including glomeruludonephritis syndrome, glomeruludonephritis and associated with antineutrophilic cytoplasmic antibodies (ANCA) glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, colitis of undetermined etiology and parasitic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, chondritis, dystrophy and / or cartilage destruction d, fibrotic disorders (including various types of liver and lung fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy) and organ transplant rejection (including rejection allograft kidney).

Neurological and neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures, and epilepsy.

Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular heartbeats (eg, in heart failure), and sexual dysfunction (including erectile dysfunction and female sexual dysfunction). Modulators of TNFa function can also be used to treat and / or prevent myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia, and metabolic syndrome.

Ophthalmic disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, nonproliferative retinopathy, and retroletal fibroplasia),

- 9,036289 macular edema (including diabetic macular edema), age-related macular degeneration (ARMD), vascularization (including corneal vascularization and neovascularization), retinal vein occlusion, and various types of uveitis and keratitis.

Cancer disorders, which can be acute or chronic, include proliferative disorders, especially cancer and cancer-related complications (including skeletal complications, cachexia, and anemia). Specific cancer categories include hematologic malignancies (including leukemia and lymphoma) and non-haematologic malignancies (including solid tumors, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma, and renal cell carcinoma). Chronic leukemia can be myeloid or lymphoid. The range of leukemias includes lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic / lymphoid leukemia (CLL), hairy cell leukemia, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), myelodysplastic syndrome, myelodysplastic syndrome acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, acute megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia and erythroleukemia. A variety of lymphomas include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALTI lymphoma, and marginal zone lymphoma. The range of non-hematological malignancies includes cancers of the prostate, lung, breast, rectum, colon, lymph nodes, bladder, kidney, prostate, liver, ovaries, uterus, cervix, brain, skin, bone, stomach and muscles. Modulators of TNFa function can also be used to enhance the safety of active anti-cancer effects of TNF (see F.V. Hauwermeiren et al., J. Clin. Invest., 2013, 123, 2590-2603).

The present invention also provides a pharmaceutical composition which contains a compound of the present invention as described above, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers.

The pharmaceutical compositions of the present invention may be in a form suitable for oral, buccal, parenteral, nasal, topical, ocular or rectal administration, or in a form suitable for administration by inhalation or insufflation.

Pharmaceutical compositions for oral administration may be, for example, in the form of tablets, lozenges or capsules, prepared by conventional techniques using pharmaceutically acceptable excipients such as binders (eg, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (eg lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (such as magnesium stearate, talc or silicon dioxide); leavening agents (such as potato starch or sodium starch glycolate); or wetting agents (eg sodium lauryl sulfate). Tablets can be coated using techniques well known in the art. Liquid preparations intended for oral administration may be, for example, in the form of solutions, syrups or suspensions, or they may be a dry preparation for reconstitution with water or other suitable diluent prior to use. Such liquid preparations can be prepared according to conventional techniques using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous solvents or preservatives. These formulations may also contain buffering salts, flavors, colors or sweeteners, as appropriate.

Formulations for oral administration can be formulated to provide controlled release of the active compound.

Compositions for buccal administration may be, for example, in the form of tablets or lozenges prepared in the usual manner.

The compounds of formula (I) can be formulated for parenteral administration by injection, for example by bolus injection or by infusion. Formulations for injection can be supplied in unit dosage form, for example, in glass ampoules or in multi-dose containers, for example in glass vials. Compositions for injection may take such forms as suspensions, solutions or emulsions in oil or aqueous diluents, and may contain formulation agents such as suspending, stabilizing, preserving and / or dispersing agents. Alternatively, the active ingredient may be in powder form for pre-use reconstitution with a suitable diluent, for example sterile pyrogen-free water.

In addition to the formulations described above, the compounds of formula (I) can also be formulated as depot preparations. Such sustained release formulations can be administered by implantation or intramuscular injection.

- 10 036289

In the case of nasal administration or administration by inhalation, the compounds of the present invention can be conveniently formulated as spraying materials using pressure packs or nebulizer devices using a suitable propellant, for example, dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

If desired, the compositions can be used in a package or dispenser, which can include one or more unit dosage forms containing the active ingredient. Administration instructions may be included with the package or dispensing device.

For topical administration, the compounds for use in the present invention can be formulated in a conventional manner as a suitable ointment containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Preferred carriers include, for example, mineral oil, liquid petroleum products, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifiable wax, and water. Alternatively, the compounds for use in the present invention can be formulated in a suitable lotion containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Preferred carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol, and water.

In the case of ophthalmic administration, the compounds for use in the present invention can conveniently be formulated as micronized suspensions in isotonic, pH-appropriate, sterile saline, without or with the addition of a preservative such as a bactericidal or fungicidal agent, for example phenylmercuronitrate. , benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration, the compounds may be formulated as an ointment, such as petroleum jelly.

In the case of rectal administration, the compounds for use in the present invention can be formulated as suppositories in a conventional manner. They can be prepared by mixing the active ingredient with a suitable non-irritating inert excipient which is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax, and polyethylene glycols.

The amount of compound to be used in the present invention required to prevent or treat a particular condition will vary depending on the compound selected and the condition of the patient being treated. Typically, however, daily dosages may be from about 10 ng / kg to 1000 mg / kg, usually from 100 ng / kg to 100 mg / kg, for example, from about 0.01 to 40 mg / (kg body weight) by oral or buccal administration, from about 10 ng / kg to 50 mg / (kg body weight) when administered parenterally, and from about 0.05 to about 1000 mg, for example, from about 0.5 to about 1000 mg, when administered nasally or by inhalation or blowing.

If necessary, the compound of the present invention can be co-administered with another pharmaceutically active agent, for example, an anti-inflammatory agent such as methotrexate or prednisolone.

It will be apparent to those skilled in the art that there are different synthetic routes that can lead to the compounds of the present invention. The following procedures are intended to illustrate some of these synthetic routes, but should in no way be construed as limiting how the compounds of the present invention should be prepared.

Compounds of formula (I) above, in which n is an integer equal to 1, X is -NH or oxygen, E is -NH ₂ or -OH, respectively, R ⁴ is hydrogen and R ¹ , R ² , R ³ , R ^5a and R ^5b are as defined above, can be prepared by a procedure which involves reacting an intermediate of formula (III) with a compound of formula Y- (CO) -H in which Y is as defined above, or with an appropriate dialkyl acetal, for example dimethyl acetal.

(III)

When R ^5a and R ^5b are hydrogen and E is —NH ₂ , the conversion is usually carried out in the presence of an acid, for example p-toluenesulfonic acid, or in the presence of a salt, for example magnesium chloride, in a suitable solvent, for example toluene or acetonitrile, at elevated temperature ...

- 11 036289

Alternatively, if the dimethyl acetal of the compound Y- (CO) -H is used, the reaction can usually be carried out in the presence of pyridinium-p-toluenesulfonate in a suitable solvent, for example acetonitrile, using microwave irradiation according to the Pictet-Spengler oxa reaction.

The dimethyl acetal of the compound Y- (CO) -H can usually be prepared, for example, by reacting Y- (CO) -H with trimethyl orthoformate in the presence of ammonium chloride in a suitable solvent such as methanol.

Intermediates of formula (III), in which E is —OH, can be prepared by a procedure that involves the reduction of an intermediate of formula (IV) in which R ^k is ^ - ^ - alkyl and R ¹ , R ² , R ³ , R ^5a and R ^5b are as defined above.

The reaction is usually carried out by treatment with a suitable reducing reagent, for example, diisobutylaluminium hydride, in a suitable solvent, for example, THF (tetrahydrofuran).

Intermediates of formula (III) in which E is —NH ₂ are prepared from intermediates of formula (III) in which E is —OH in a two-step reaction.

The first step is carried out by treating an intermediate of formula (III) in which E is —OH with phthalimide, triphenylphosphine and diisopropylazadicarboxylate in a suitable solvent, for example THF. The compound thus obtained is further treated with hydrazine in a suitable solvent, eg methanol, at elevated temperature to give the desired intermediate of formula (III), in which E is —NH ₂ .

Intermediates of formula (IV) as defined above can be prepared by a procedure involving the reaction of intermediates of formula (V) in which R ¹ , R ² and R ³ are as defined above with intermediates of formula (VI), in wherein R ^5a , R ^5b and R ^k are as defined above and L ¹ is a suitable leaving group, for example a halogen atom.

(V) (VI) (IV)

The reaction is usually carried out at elevated temperature in a suitable solvent, for example a C ₁ -alkanol such as ethanol or an ether such as 1,4-dioxane or dimethoxyethane.

Intermediates of formula (IV) in which R ¹ is hydrogen can be converted to the corresponding intermediate in which R ¹ is bromine or chlorine by treatment with N-chloro or N-bromosuccinimide in a suitable solvent, for example acetonitrile.

Compounds of formula (I) above in which n is an integer of 1, X is methylene and R ⁴ is hydroxy can be prepared by a procedure which involves reacting an intermediate of formula (VII) with a compound of formula Y-Mg-X ¹ in which X ¹ is halogen, eg chlorine, using Grignard reaction conditions known to one skilled in the art.

Y (VII) (I)

Compounds of formula (I) in which R ⁴ is hydroxy can then be converted to a compound of formula (I) in which R ⁴ is hydrogen by deoxygenation in a manner similar to that described in Barton, DHR et al. in J. Chem. Soc., Perkin Trans. 1 (1975), 16: 15741585, or any other technique known to a person skilled in the art.

Compounds of formula (VII) can be prepared by a procedure which involves reacting an intermediate of formula (V) with an intermediate of formula (VIII) in which L ² is

- 12 036289 leaving group, for example halogen, preferably bromine.

R ³

(V) (VIII)

The reaction is usually carried out in a polar solvent such as ethanol at elevated temperature.

Compounds of formula (I) above, in which n is an integer of 0, X is methylene, R ⁴ is hydrogen, R ^5a is hydroxy and R ^5b is hydrogen, can be prepared from intermediates of formula (IX)

in which R ¹ , R ² , R ³ and Y are as defined above; by reduction of the carbonyl moiety according to methods known to the person skilled in the art) in the art.

Intermediates of formula (IX) can be prepared by a procedure that involves intramolecular cyclization of an intermediate of formula (X)

in which Q ¹ is an electron-withdrawing group, preferably an ester moiety, R ^k , R ¹ , R ² , R ³ and Y are as defined above.

The reaction is usually carried out in the presence of a base in a suitable solvent at elevated temperature.

Intermediates of formula (X) can be prepared in a multi-step procedure involving the reaction of an intermediate of formula (XI)

in which Q ¹ is —COOH, Q ² is a protecting group and R ¹ , R ² , R ³ and Y are as defined above.

In the first step, the protecting group is removed from the intermediate of formula (XI) and then the resulting alkoxy moiety is oxidized to give the corresponding carboxyl moiety.

The resulting intermediate of formula (XI), in which Q ¹ is as defined above and —CH2 — OQ ² is —COOH is esterified according to methods known to the person skilled in the art to give the corresponding intermediate of formula (X).

Intermediates of formula (XI) described above can be prepared by a procedure that involves reacting an intermediate of formula (XII)

in which R ¹ , R ³ , R ⁴ and Q are as defined above; with an intermediate product of the formula Y-CO-H, in the presence of an acid

Meldrum, in a manner similar to that described in international patent application WO 2009/156091, or in the publication of M. Kerr et al. in J. Org. Chem 2013, 78, 10534.

The reaction is usually carried out in a suitable solvent, eg acetonitrile, in the presence of a Lewis acid, eg scandium triflate, or in the presence of an organic catalyst, eg proline, and magnesium sulfate at elevated temperatures, eg 80 ° C.

Intermediates of formula (XII) can be prepared by a procedure involving reduction of an intermediate of formula (XIII)

- 13 036289

R ³

R ⁴ (χπΐ) in which R ¹ , R ³ , R ⁴ and R ^k are as defined above, followed by the introduction of a suitable protecting group into the resulting alcohol according to methods known to the person skilled in the art.

Intermediates of formula (XIII) can be prepared by a procedure involving reacting an intermediate of formula (V) with an intermediate of formula (XIV)

R ³

(V) (XIV) in which L ¹ , R ¹ , R ² , R ³ and R ^k are as defined above.

The reaction is usually carried out in a manner analogous to that described for the reaction of an intermediate of formula (V) with an intermediate of formula (VI).

The reference to a compound of formula (I) given below in the present invention is to be understood as including all possible subclasses and subgroups described above.

A compound of formula (I) which contains a carbonyl group, in particular a compound of formula (I) in which R ^5a and R ^5b together with the carbon atom to which they are attached form a carbonyl, can be converted into the corresponding compound in which R ^5a is hydroxy and R ^5b is hydrogen, using, for example, tri-sec-butyl lithium borohydride or sodium borohydride, in a suitable solvent, for example THF.

A compound of formula (I) which contains a carbonyl group, in particular a compound of formula (I) in which R ^5a and R ^5b together with the carbon atom to which they are attached form a carbonyl, can be converted into the corresponding compound in which R ^5a is trifluoromethyl; and R ^5b is hydroxy, by treatment with trifluoromethylsilane at room temperature in a suitable solvent, eg dimethoxyethane.

A compound of formula (I) which contains a carbonyl group, in particular a compound of formula (I) in which R ^5a and R ^5b together with the carbon atom to which they are attached form a carbonyl, can be converted into the corresponding compound in which R ^5a is (C1-C6 alkyl) sulfonylaryloxytrifluoromethyl and R ^5b is hydrogen, by treatment with (C1-C6 alkyl) sulfonylphenol, in the presence of diisopropyl 1,2-diazenedicarboxylate, in a suitable solvent, for example THF.

A compound of formula (I) which contains a carbonyl group, in particular a compound of formula (I) in which R ^5a and R ^5b together with the carbon atom to which they are attached form a carbonyl, can be converted into a corresponding compound in which R ^5a and R ^5b together with the carbon atom to which they are attached represent —C═N — OH, by treatment, for example, with hydroxylamine chloride in the presence of pyridine and in the presence of a suitable solvent such as ethanol.

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound in which R ^5a and R ^5b are hydrogen, for example by treatment iodotrimethylsilane in a suitable solvent such as acetonitrile.

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound in which R ^5a is —NH2 and R ^5b is hydrogen, by a two-step procedure, for example by (i) treatment with diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene. This reaction is usually carried out at 0 ° C in THF; (ii) subsequent aza Wittig reaction using PPh3 in a suitable solvent, for example a mixture of water and toluene.

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound in which R ^5a is —F and R ^5b is hydrogen by treatment with diethylamine sulfur trifluoride in a suitable solvent, for example THF.

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound of formula (I) in which R ^5a is C1-C ₄ - alkyl, for example methyl, and R ^5b is hydrogen, by treatment, for example, with alkyl magnesium bromide in a suitable solvent, for example diethyl ether.

- 14 036289

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound in which R ^5a is C | -C. - _G alkoxy ... for example, methoxy and R ^5b is hydrogen, by treatment with a base, eg sodium hydride, in a suitable solvent, eg THF, in the presence of a suitable alkylating reagent such as an alkyl halide, eg methyl iodide.

The compound of formula (I), which contains a hydroxy group, can be alkylated by treatment with a suitable alkyl halide in the presence of a base, for example sodium hydride or silver oxide.

The compound of formula (I), which contains a hydroxy group, can be converted to the corresponding fluoro-substituted compound by treatment with diethylaminosulfur trifluoride (DATS) or bis (2methoxyethyl) aminosulfur trifluoride (BATS).

The compound of formula (I), which contains a hydroxy group, can be converted to the corresponding difluoro-substituted compound in a two-step procedure, which includes: (i) treatment with an oxidizing reagent, for example, manganese dioxide; and (ii) treating the carbonyl-containing compound thus obtained with DATS.

A compound of formula (I) which contains a hydroxy group, in particular a compound of formula (I) in which R ^5a is hydroxy and R ^5b is hydrogen, can be converted to the corresponding compound of formula (I) containing a (aminocarbonyl) methoxy group in a two-step procedure which comprises (i) treating with bromoacetonitrile in a suitable solvent, eg THF, at low temperature in the presence of sodium hydride, and (ii) treating the nitrile compound thus obtained with a solution of hydrobromic acid in acetic acid.

A compound of formula (I) which contains an N — H moiety can be alkylated by treatment with a suitable alkyl halide, usually at elevated temperature, in an organic solvent such as acetonitrile; or at ambient temperature in the presence of a base, for example an alkali metal carbonate such as potassium carbonate or cesium carbonate, in a suitable solvent, for example a dipole aprotic solvent such as Ν,-dimethylformamide. Alternatively, a compound of formula (I) which contains an NH moiety can be alkylated by treatment with a suitable alkyl tosylate in the presence of a base, for example an inorganic base such as sodium hydride or an organic base such as 1,8-diazabicyclo [5.4.0] undec -7-en (DBU).

The compound of formula (I), which contains an N — H moiety, can be methylated by treatment with formaldehyde in the presence of a reducing reagent, for example sodium triacetoxyborohydride.

A compound of formula (I) which contains an N — H moiety can be acylated by treatment with a suitable acid chloride, for example acetyl chloride, or with a suitable carboxylic acid anhydride, for example acetic anhydride, usually at ambient temperature in the presence of a base, for example an organic base such as triethylamine.

A compound of formula (I) which contains an NH moiety can be converted to the corresponding compound in which the nitrogen atom is substituted with a C ₁ -C ₆ alkylsulfonyl group, for example a methylsulfonyl group, by treatment with a suitable C ₁ -C ₆ alkylsulfonyl chloride, for example methanesulfonyl chloride, or a suitable C ₁ -C ₆ alkyl sulfonic anhydride, for example methanesulfonic anhydride, usually at ambient temperature in the presence of a base, for example an organic base such as triethylamine or Ν, Ν-diisopropylethylamine.

A compound of formula (I) substituted with an amino group (—NH2) can be converted to the corresponding compound substituted with a C ₁ -C ₆ alkylsulfonylamino group, for example methylsulfonylamino or bis [(C ₁ -C ₆ ) alkylsulfonyl] amino, for example bis (methylsulfonyl) amino eg bis (methylsulfonyl) amino group, by treatment with a suitable C ₁ -C ₆ alkylsulfonyl halide, eg C ₁ -C ₆ alkylsulfonyl chloride, such as methanesulfonyl chloride. Similarly, a compound of formula (I) substituted with a hydroxy group (-OH) can be converted to a corresponding compound substituted with a C ₁ -C ₆ alkylsulfonyloxy group, for example methylsulfonyloxy, by treatment with a suitable C ₁ -C ₆ alkylsulfonyl halide, for example C ₁ -C _6- alkylsulfonyl chloride such as methanesulfonyl chloride.

The compound of formula (I) containing the —S— moiety can be converted to the corresponding compound containing the —S (O) - moiety by treatment with 3-chloroperoxybenzoic acid. Likewise, the compound of formula (I) containing the —S (O) - moiety can be converted to the corresponding compound containing the —S (O) ₂ - moiety by treatment with 3-chloroperoxybenzoic acid. Alternatively, the compound of formula (I) containing the —S— moiety can be converted to the corresponding compound containing the —S (O) ₂ - moiety by treatment with Oxone® (potassium peroxymonosulfate).

The compound of formula (I) containing an aromatic nitrogen atom can be converted to the corresponding N-oxide derivative by treatment with 3-chloroperoxybenzoic acid.

The compound of formula (I), which contains a carbonyl, can be converted to the corresponding alcohol by treatment with a suitable borohydride, for example, lithium tri-sec-butyl borohydride or sodium borohydride, in a suitable solvent, for example THF.

The bromophenyl derivative of formula (I) can be converted into the corresponding optionally substituted 2-oxopyrrolidin-1-ylphenyl or 2-oxooxazilidin-3-ylphenyl derivative by treatment with pyrrolidin-2-one or oxazolidin-2-one, or appropriately substituted analogue. The reaction is usually carried out at elevated temperature in the presence of copper iodide ([), transKI-dimethylcyclohexane-1.2-diamine, and an inorganic base such as potassium carbonate.

A compound of formula (I) in which R ¹ is halogen, for example bromine, can be converted to the corresponding compound in which R ¹ is an optionally substituted aryl or heteroaryl moiety by treatment with a suitably substituted aryl or heteroaryl boronic acid or a cyclic ester thereof, prepared with an organic diol such as pinacol, 1,3 propanediol or neopentyl glycol. The reaction is usually carried out in the presence of a transition metal catalyst, for example, [1, G-bis (diphenylphosphino) ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium (0), bis [3 - (diphenylphosphanyl) cyclopenta-2 complex, 4-diene-1 yl] iron-dichloropalladium-dichloromethane, and bases, for example, an inorganic base such as sodium carbonate or potassium carbonate or potassium phosphate. This reaction can usually be carried out in 1,4 dioxane with or without microwave radiation. Alternatively, the above reaction can be carried out in the presence of a complex of tris (dibenzylideneacetone) dipalladium (0) chloroform and dicyclohexyl- [2- (2,4,6-triisopropylphenyl) phenyl] phosphane in a polar solvent such as n-butanol at high temperature ...

A compound of formula (I) in which R ¹ is halogen, for example bromine, can be converted to the corresponding compound in which R ¹ is an optionally substituted aryl, heteroaryl, or heterocycloalkenyl moiety in a two-step procedure that includes: (i) reacting with bis (pinacolato) diboron or bis (neopentylglycolate) diboron; and (ii) reacting the compound thus obtained with an appropriately functionalized halogen- or tosyloxy-substituted aryl, heteroaryl, or heterocycloalkenyl derivative. Step (i) is usually carried out in the presence of a transition metal catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (11) or bis [3- (diphenylphosphanyl) cyclopenta2,4-diene-1-yl complex ] iron-dichloropalladium-dichloromethane. Step (ii) is typically carried out in the presence of a transition metal catalyst such as tetrakis- (triphenylphosphine) palladium (0) or a bis [3 - (diphenylphosphanyl) cyclopenta-2,4-diene-1-yl] iron-dichloropalladium complex dichloromethane; and bases such as an inorganic base such as sodium carbonate or potassium carbonate.

A compound of formula (I) in which R ¹ is halogen, for example bromine, can be converted to the corresponding compound in which R ¹ is an optionally substituted C ₂ -C ₆ alkynyl moiety by treatment with an appropriately substituted alkyne derivative, for example 2-hydroxybut -3-different. The reaction is usually carried out using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0), usually in the presence of copper (1) iodide and a base such as an organic base such as triethylamine.

A compound of formula (I) in which R ¹ is halogen, for example bromine, can be converted to the corresponding compound in which R ¹ is an optionally substituted imidazol-1-yl moiety by treatment with a suitably substituted imidazole derivative, usually in the presence of copper acetate (P) and an organic base such as Ν, Ν, Ν ', Ν'-tetramethylethylenediamine (TMEDA).

A compound of formula (I) in which R ¹ is halogen, eg bromine, can be converted to the corresponding compound in which R ¹ is 2- (methoxycarbonyl) ethyl in a two-step procedure which comprises: (i) reaction with methyl acrylate; and (ii) catalytic hydrogenation of the alkenyl derivative thus obtained, typically by treatment with a hydrogenation catalyst such as palladium on charcoal, under a hydrogen atmosphere. Step (i) is typically carried out in the presence of a transition metal catalyst such as palladium (11) acetate or bis (dibenzylideneacetone) palladium (0) and a reagent such as tri (ortho-tolyl) phosphine.

Typically, a compound of formula (I) containing a —C═C— group can be converted to a corresponding compound containing a —CH — CH— group by catalytic hydrogenation, usually by treatment with a hydrogenation catalyst such as palladium on charcoal under a hydrogen atmosphere, optionally in the presence of a base, for example an alkali metal hydroxide such as sodium hydroxide.

A compound of formula (I) in which R ¹ is 6-methoxypyridin-3-yl can be converted to the corresponding compound in which R ¹ is 2-oxo (1H) pyridinyl by treatment with pyridine hydrochloride; or by heating with an inorganic acid such as hydrochloric acid. By using a similar procedure, the compound of formula (I) in which R ¹ is 6methoxy-4-methylpyridin-3-yl can be converted to the corresponding compound in which R ¹ is 4-methyl-2-oxo-1,2-dihydropyridine- 5-yl; and a compound of formula (I) in which R ¹ is 6methoxy-5-methylpyridin-3-yl can be converted to the corresponding compound in which R ¹ is 3-methyl-2-oxo-1,2-dihydropyridin-5-yl ...

The compound of formula (I) in which R ¹ is 2-oxo-1,2-dihydropyridin-5-yl can be converted to the corresponding compound in which R ¹ is 2-oxopiperidin-5-yl by catalytic hydrogenation, usually by treatment with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide (! Y).

A compound of formula (I) containing an ester moiety, for example a C ₂ -C ₆ alkoxycarbonyl group such as a methoxycarbonyl or ethoxycarbonyl group, can be converted to the corresponding compound containing a carboxy group (—CO2H) by treatment with an acid, for example, an inorganic acid such as hydrochloric acid.

The compound of formula (I) containing the No. (tert-butoxycarbonyl) moiety can be converted to the corresponding compound containing the N — H moiety by treatment with an acid, for example an inorganic acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

A compound of formula (I) containing an ester moiety, for example a C ₂ -C ₆ alkoxycarbonyl group such as a methoxycarbonyl or ethoxycarbonyl group, can alternatively be converted to the corresponding compound containing a carboxy group (—CO2H) by treatment with a base, for example an alkali metal hydroxide, selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.

A compound of formula (I) containing a carboxy group (—CO ₂ H) can be converted to the corresponding compound containing an amide moiety by treatment with a suitable amine in the presence of a condensing reagent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.

A compound of formula (I) containing a carbonyl (C = O) moiety can be converted to the corresponding compound containing a —C (CH ₃ ) (OH) - moiety by treatment with methylmagnesium bromide. Likewise, a compound of formula (I) containing a carbonyl (C = O) moiety can be converted to a corresponding compound containing a —C (CF ₃ ) (OH) - moiety by treatment with (trifluoromethyl) trimethylsilane and cesium fluoride. The compound of formula (I), the carbonyl (C = O) moiety, can be converted to the corresponding compound containing the —C (CH2NO2) (OH) - moiety by treatment with nitromethane.

A compound of formula (I) containing a hydroxymethyl moiety can be converted to the corresponding compound containing a formyl (—CHO) moiety by treatment with an oxidizing reagent such as Dess-Martin periodinane. The compound of formula (I) containing a hydroxymethyl moiety can be converted to the corresponding compound containing a carboxy group by treatment with an oxidizing reagent such as tetrapropylammonium perruthenate.

A compound of formula (I) in which R ¹ is a substituent containing at least one nitrogen atom such that the substituent is bonded to the rest of the molecule through a nitrogen atom can be prepared by reacting a compound of formula (I) in which R ¹ is halogen, for example bromine, with the corresponding compound of the formula R ¹ -H [eg 1- (pyridin-3-yl) piperazine or morpholine]. The reaction is usually carried out using a transition metal catalyst such as tris (dibenzylideneacetone) dipalladium (0) in the presence of an amination ligand such as 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl (XPhos) or 2,2'- bis (diphenylphosphino) -1,1'binaphthalene (BINAP), or Xantphos, and a base, for example, an inorganic base such as sodium t-butoxide or cesium fluoride. Alternatively, the reaction can be carried out using palladium diacetate, in the presence of a reagent such as [2 ', 6'-bis (propan-2-yloxy) biphenyl-2yl] (dicyclohexyl) phosphane, and a base such as an inorganic base such as carbonate cesium.

The compound of formula (I) containing an oxo group can be converted to the corresponding compound containing an ethoxycarbonylmethylidene moiety by treatment with triethylphosphonoacetate in the presence of a base such as sodium hydride.

The compound of formula (I) containing the C — OH moiety can be converted to the corresponding compound containing the C — F moiety by treating with difluoro (morpholino) sulfonium tetrafluoroborate in a suitable solvent, for example dichloromethane, at low temperature.

If a mixture of products is formed using any of the above methods for preparing the compounds of the present invention, the desired product can be isolated from it at a suitable stage using conventional techniques such as preparative HPLC (high performance liquid chromatography) or column chromatography using, for example, silicon dioxide and / or alumina together with a suitable solvent system.

If a mixture of stereoisomers is formed using the procedures described above for the preparation of the compounds of the present invention, these isomers can be separated using conventional procedures. In particular, when a particular enantiomer of a compound of formula (I) is desired, it can be prepared from the corresponding mixture of enantiomers by any conventional enantiomeric resolution technique. For example, diastereoisomeric derivatives, eg salts, can be prepared by reacting a mixture of enantiomers of formula (I), eg a racemate, with a corresponding chiral compound, eg a chiral base. The diastereoisomers can then be separated by any of the usual techniques, for example by crystallization, and the desired enantiomer isolated, for example, by treatment with an acid if the diastereoisomer is a salt. In another separation procedure, the racemate of formula (I) can be resolved using chiral HPLC. In addition, if necessary, a particular enantiomer can be obtained by using a suitable chiral intermediate in one of the procedures described above. Alternatively, a particular enantiomer can be obtained by performing an enantiomerically specific enzymatic biological conversion, for example, hydrolysis of an ester using an esterase followed by purification of only the enantiomerically pure acid formed as a result of hydrolysis from the unreacted antipode, the ester. If a particular geometric isomer of the present invention is desired, chromatography, recrystallization and other conventional separation techniques can be used for intermediates or end products.

During any of the above synthetic sequences, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved in the reactions. This can be accomplished using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 ^rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage by methods known in the art.

The compounds of the present invention effectively inhibit TNFa activity in a commercially available HEK-293-derived reporter cell line known as HEK-Blue ™ CD40L. The cells of this line are stable transfectants expressing SEAP (secreted embryonic alkaline phosphatase) when regulated by a minimal IFNe promoter fused to 5 NF-kB binding sites. The secretion of SEAP by these cells by TNFa is stimulated in a concentration-dependent manner. According to the HEK-293 biological assay, also referred to in the present invention as a reporter gene assay, some compounds of the present invention have an IC ₅₀ value of 50 μM or less, typically 20 μM or less, more often 5 μM or less. more often equal to 1 μM or less, preferably equal to 500 nM or less, ideally equal to 100 nM or less, and more preferably equal to 25 nM or less (it will be obvious to a person skilled in the art that a lower IC50 value represents a more active compound).

Certain compounds of the present invention are effective in inhibiting the binding of the fluorescent conjugate to TNFa when assayed using the fluorescence polarization assay described in the present invention. In fact, when investigated by this, the compounds of the present invention have an IC ₅₀ value of 50 μM or less, usually equal to 20 μM or less, more often equal to 5 μM or less, more often equal to 1 μM or less, preferably equal to 500 nM or less, ideally equal to 100 nM or less, and more preferably equal to 25 nM or less (as above, it will be obvious to a person skilled in the art that a lower IC ₅₀ value represents a more active compound).

The examples below illustrate the preparation of the compounds of the present invention.

The compounds shown in the examples were tested using one or both of the following assay procedures.

Fluorescence polarization analysis

Obtaining compound (A).

1- (2,5-Dimethylbenzyl) -6- [4- (piperazin-1-ylmethyl) phenyl] -2- (pyridin-4-ylmethyl) -1Hbenzimidazole, hereinafter referred to as compound (A) in the present invention, can be obtained by the technique described in Example 499 in WO 2013/186229 (published December 19, 2013); or by a similar technique.

Preparation of a fluorescent conjugate

Compound (A) (27.02 mg, 0.0538 mmol) was dissolved in DMSO (2 ml). 5 - (- 6) Carboxyfluorescein succinyl ether (24.16 mg, 0.0510 mmol) (Invitrogen catalog number: C1311) was dissolved in DMSO (1 ml) to give a bright yellow solution. The two solutions were mixed at room temperature, the mixture turned red. The mixture was stirred at room temperature. Shortly after mixing, a 20 μl aliquot was taken and diluted in 80:20 AcOH: H2O for LC-MS analysis using a 1200RR-6140 LC-MS system. The chromatogram revealed 2 peaks with similar elution times at retention times equal to 1.42 and 1.50 min, both corresponding to the mass (M + H) + = 860.8 at. units masses corresponding to two products formed with 5 and 6-substituted carboxyfluorescein group. Another peak at a retention time of 2.21 min corresponded to the mass (M + H) + = 502.8 at. units mass corresponding to compound (A). No peaks of unreacted 5 (-6) carboxyfluorescein succinyl ether were found. The peak areas were 22.0, 39.6 and 31.4% for the three signals, indicating a 61.6% conversion of the two isomers to the desired fluorescent conjugate at this time point. Additional

- 18,036289 aliquots of 20 μl were taken after a few hours and then, after stirring overnight, were diluted as above and analyzed by LC-MS. At these time points, the conversion was found to be 79.8 and 88.6%, respectively. The mixture was purified using a preparative HPLC system with UV detection. The combined purified fractions were freeze dried to remove excess solvent. After freeze drying, an orange solid (23.3 mg) was isolated, equivalent to 0.027 mmol of fluorescent conjugate, corresponding to an overall yield of 53% purified by preparative HPLC.

Inhibition of the binding of the fluorescent conjugate to TNFa

Compounds were tested at 10 concentrations, starting at 25 μM, with a final concentration of DMSO in the assay of 5%, by pre-incubation with TNFa for 60 min at ambient temperature in 20 mM Tris (Tris - Tris (hydroxymethylaminomethane)), 150 mM NaCl, 0.05% Tween 20, then the fluorescent conjugate was added and additionally incubated at ambient temperature for 20 hours.The final concentrations of TNFa and fluorescent conjugate were 10 nM and 10 nM, respectively, with a total volume of the test solution equal to 25 μl. Plates were read in a plate reader capable of detecting fluorescence polarization (eg, Analyst HT reader; or Envision reader). IC _{50 was} calculated using XLfit ™ (4-parameter logistic model) using ActivityBase software.

It was found that all of the compounds of the appended examples had IC ₅₀ values of 50 μM or less from a study by fluorescence polarization analysis.

Reporter Gene Research

Inhibition of TNFa-induced NF-kB activation

Stimulation of HEK-293 cells with TNFα leads to activation of the NF-kB pathway. The reporter cell line used to determine TNFa activity was purchased from InvivoGen. HEK-Blue ™ CD40L is a stable transfected HEK-293 cell line expressing SEAP (Secreted Embryonic Alkaline Phosphatase) under the control of an IFNe minimal promoter fused to the five NF-kB binding sites. The secretion of SEAP by these cells is stimulated in a concentration-dependent manner by TNFa at an EC ₅₀ of 0.5 ng / ml for human TNFa. Dilutions of compounds were prepared from 10 mM stock solutions in DMSO (the final concentration of DMSO in the analysis was 0.3%) and a 10-point relationship was obtained for 3-fold serial dilutions (for example, final concentrations equal to 30,000 to 2 nM). The diluted compound was preincubated with TNFa for 60 min and then placed in a 384 well microtiter plate and incubated for 18 hours. The final concentration of TNFa in the assay plate was 0.5 ng / ml. SEAP activity was determined in the supernatant using a colorimetric assay substrate, eg, QUANTI-Blue ™ or HEK-Blue ™ detection media (InvivoGen). Percent inhibitions for compound dilutions were calculated ranging from control DMSO and maximum inhibition (with excess control) and IC50 values were calculated using XLfit ™ (4-parameter logistic model) using ActivityBase software.

It was found that according to the study using the analysis of the reporter gene, some of the compounds shown in the accompanying examples had IC ₅₀ values equal to 50 μM or less.

Examples of

Nomenclature

Compound names obtained using ACD / Name Batch (Network) software version 12.0.

Abbreviations

DXM - dichloromethane

EtOAc - ethyl acetate

DMF - N.N-dimeth'ylformamide

MeOH - methanol

DMSO - dimethyl sulfoxide

SiO ₂ - silicon dioxide

Et ₂ O - diethyl ether h - hour (s)

THF - tetrahydrofuran

AcOH - acetic acid

CT - room temperature

VU - retention time br. - wide

MeCN - acetonitrile

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M - mass

EtOH - ethanol brine - saturated aqueous sodium chloride solution

HPLC - high performance liquid chromatography

LCMS - liquid chromatography-mass spectrometry

ER + - electrospray ionization in positive ion mode

TEA - triethylamine

DIPEA - UC-diisopropylethylamine

DIAD - diisopropyl- (E) -1,2-diazenedicarboxylate

CDI - carbonyldiimidazole

DIBAL-N - diisobutylaluminum hydride bs. - wide singlet

Boc ₂ O - di-tert-butyl dicarbonate

DME - dimethoxyethane

TLC - thin layer chromatography

A methanolic ammonia solution was prepared by mixing 100 ml of an aqueous NH4OH solution (37% w / w) and 900 ml of MeOH.

Analysis conditions

All NMR (nuclear magnetic resonance) spectra were recorded at 300 MHz or 400 MHz.

All reactions in which reagents sensitive to air or moisture were used were carried out under a nitrogen atmosphere using dried solvents and glassware.

LCMS data for all compounds were obtained using the procedure below.

Method 1:

Waters Acquity-SQD, Waters Acquity UPLC VEN C18 Column, 2.1x50mm, 1.7um

Mobile phase A: 10 mM ammonium formate + 0.1% ammonia

Mobile phase B: 95% MeCN + 5% H ₂ O + 0.1% ammonia

Gradient program (flow rate: 1.0 ml / min, column temperature: 40 ° C):

Time A, %IN, 0.00 95 5 0.50 95 5 1.75 5 95 2.00 5 95 2.25 95 5

Method 2 (M2):

Waters Acquity-SQD, Waters Acquity UPLC VEN C18 Column, 2.1x50mm, 1.7um

Mobile phase A: water + 0.05% formic acid

Mobile phase B: MeCN + 0.035% formic acid

Gradient program (flow rate: 0.9 ml / min, column temperature: 55 ° C):

Time A,% B, 0.00 95 5 2.00 5 95 2.60 5 95 2.70 95 5 3.00 95 5

Method 3:

Column: Waters XSelect (C18, 30x2.1mm, 3.5um)

Flow rate: 1 ml / min, column temperature: 35 ° C

Eluent A: 0.1% formic acid in acetonitrile

Eluent B: 0.1% formic acid in water

Linear gradient mode: t = 0 min 5% A, t = 1.6 min 98% A, t = 3 min 98% A

Detection: DDM (Diode Array Detector) (220-320 nm)

Detection: DPM (photodiode array detector) (200-400 nm)

Detection: MSD (mass selective detector) (IES (electrospray ionization) in positive / negative ion mode), mass range: 100-800.

It will be apparent to one of ordinary skill in the art that different retention times (RT) values can be obtained using different LCMS analysis conditions.

Intermediate product 1.

Ethyl 2- (6-bromimidazo [1,2-a] pyrazin-2-yl) acetate

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To a solution of 5-bromo-2-aminopyrazine (2.59 g, 14.89 mmol) in EtOH (100 ml) was added ethyl 4-chloro-3oxobutanoate (2.62 g, 15.93 mmol). The reaction mixture was boiled under reflux for 18 hours. The reaction mixture was cooled to RT and water (200 ml) was added, the mixture was extracted with DCM (2x200 ml). The organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a brown solid (0.65 g, 15%). LCMS (ER +): 284.0 / 286.0 (M + H) ⁺ .

Intermediate product 2.

2- (6-Bromimidazo [1,2-a] pyrazin-2-yl) ethanol

To a solution of intermediate 1 (1.0 g, 3.52 mmol) in THF (30 ml) at -78 ° C was added DIBAL-H (9.00 ml, 9.00 mmol) dropwise. The reaction mixture was stirred at a temperature of -78 to -40 ° C for 4 h. The reaction mixture was treated with excess Na ₂ SO ₄ -10H ₂ O and diluted with DCM (200 ml) and i-PrOH (100 ml) ... The solid was filtered off and the filtrate was concentrated in vacuo to give the title compound as a brown oil (0.68 g, 80%).

LCMS (ER +): 242.0 / 244.0 (M + H) +.

Intermediate 3.

1- (Difluoromethoxy) -2- (dimethoxymethyl) benzene

To a solution of 2- (difluoromethoxy) benzaldehyde (5.51 g, 29.05 mmol) in MeOH (20 ml) were added trimethyl orthoformate (4.13 ml, 37.76 mmol) and LiBF ₄ (0.08 g, 0.87 mmol). The reaction mixture was boiled under reflux for 4 h, cooled and treated with saturated aqueous NaHCO ₃ (50 ml), extracted with EtOAc (50 ml), dried over MgSO ₄ and concentrated in vacuo to give the title compound as a yellow oil ( 6.30 g, 100%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (dd, J 7.6, 1.5 Hz, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 7, 08 (d, J 8.1 Hz, 1H), 6.40 (t, J 74.6 Hz, 1H), 5.53 (s, 1H), 3.32 (s, 6H).

Intermediate 4.

1- [2- (Difluoromethoxy) phenyl] -8-bromo-3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine

F

To a solution of intermediate 2 (0.19 g, 0.78 mmol) in MeCN (3 ml) were added paratoluenesulfonic acid (0.01 g, 0.78 mmol) and intermediate 3 (0.17 g, 0.78 mmol ) and the reaction mixture was heated at 100 ° C for 18 h. The reaction mixture was cooled and treated with EtOAc (80 ml) and washed with water (3x10 ml). The organics were washed with brine (50 ml) and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-3% MeOH / DCM (10% NH 4 OH)) to give the title compound as a brown solid (0.06 g, 19%).

1H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 7.42 (m, 1H), 7.27 (m, 2H), 7.16 (t, J 7.3 Hz, 1H ), 6.91 (d, J 7.6 Hz, 1H), 6.58 (dd, J1 75.3 Hz, J ₂ 72.2 Hz, 1H), 6.25 (s, 1H), 4, 20 (m, 1H), 3.96 (m, 1H), 3.21 (m, 1H), 3.03 (m, 1H). LCMS (ER +): 396.0 / 398.0 (M + H) +.

Intermediate 5. Ethyl 6-bromimidazo [1,2-a] pyrazine-2-carboxylate

2-Amino-5-bromopyrazine (100 g, 575 mmol) was dissolved in anhydrous 1,4-dioxane (2 L) and ethyl bromopyruvate (155 g, 636 mmol, 100 ml) was added to the solution with mechanical stirring. The mixture was heated at 95 ° C and stirred overnight.

The mixture was cooled to room temperature and triethylamine (69.8 g, 690 mmol, 96 ml) was added. The mixture was stirred at ambient temperature for 1 hour.

The mixture was filtered through diatomaceous earth and washed with DCM / EtOH (9: 1). The filtrate was concentrated and evaporated with Et2O. The resulting residue was triturated with water and filtered, the solids were washed with water and with Et2O to give a crude solid which was purified by filtration through a thick plug of silica (~ 1 kg). The eluent was a 95: 5 DCM / EtOH mixture and after evaporation of the solvents the title compound was obtained as a beige solid (80 g).

1H NMR (400 MHz, DMSOO δ 9.10-9.03 (m, 1H), 8.93 (d, J = 1.4 Hz, 1H), 8.58 (d, J = 0.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

LCMS, Method 3, VU 1.61 min, m / z 270, 272 (M + H) +.

Intermediate 6. (6-Bromimidazo [1,2-a] pyrazin-2-yl) methanol

With mechanical stirring, a suspension of intermediate 5 (98.4 g, 364 mmol) in anhydrous THF (1800 ml) was cooled under nitrogen to -70 / -74 ° C. A 1M solution of DIBAL-N in hexanes (800 mmol, 800 ml) was added dropwise under nitrogen atmosphere over ~ 2 h. During the addition of DIBALN, the temperature of the reaction mixture was maintained at no more than -70 ° C. After the addition of DIBAL-N was complete, the reaction mixture was held at a temperature less than -70 ° C for about

- 21,036289 min and then the cooling bath was removed and the reaction mixture was allowed to slowly warm to room temperature for several hours.

The reaction was stopped by slow addition of sodium sulfate decahydrate (392 g, 1218 mmol) while cooling with an ice / water mixture. The mixture was slowly stirred overnight while maintaining the temperature <25 ° C. The mixture was filtered through a sintered glass funnel and the residue was washed several times with DCM / MeOH 1: 1 and the combined filtrates were concentrated in vacuo and evaporated with toluene to give 78.2 g of a sandy solid.

The solid was triturated with diisopropyl ether to give a solid which was isolated by filtration and washed with cold diisopropyl ether. The filtrates were concentrated in vacuo and the residue was re-triturated with diisopropyl ether to give additional solid. The combined solids were the title compound as a beige powder (66.8 g).

LCMS, Method 3, VA 0.43 min, m / z 228, 230 (M + H) +.

Intermediate 7.5-Chloro-2- (difluoromethoxy) benzaldehyde

To a solution of 5-chloro-2-hydroxybenzaldehyde (200 g, 1277 mmol) in 1,4-dioxane (800 ml) was added a solution of sodium hydroxide (307 g, 7664 mmol) in water (800 ml) and sodium dithionite (22.24 d, 128 mmol). The reaction mixture was heated to 65 ° C and chlorodifluoromethane (133 g, 1533 mmol) was blown through the reaction mixture with vigorous mechanical stirring for -30-40 min. After completion of the reaction (determined by the amount of chlorodifluoromethane used), the mixture was immediately cooled to ambient temperature with an ice / water mixture. The aqueous and organic layers were separated and the aqueous layer was extracted 3 times with diethyl ether. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as an orange oil (136 g).

Intermediate 8.

3-Bromo-6- [5-chloro-2- (difluoromethoxy) phenyl] -6,10-dihydrooxepino- [3 ', 4': 4,5] imidazo [1,2-a] pyrazin8 (7H) -one

A solution of intermediate 6 (66.5 g, 292 mmol), intermediate 7 (113 g, 437 mmol), Meldrum's acid (63 g, 431 mmol, 1.5 eq.) And ^) - pyrrolidine-2-carboxylic acid ( 1.68 g, 14.58 mmol) in anhydrous acetonitrile (1000 ml) was heated to 90 ° C and stirred under nitrogen atmosphere for 4 days. The reaction mixture was concentrated in vacuo and the residue was taken up in EtOAc. The mixture was filtered through a sintered glass funnel and the residue was washed with EtOAc. The filtrate was washed twice with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound as a dark oily solid and used in the next step without work-up.

LCMS, Method 3, RT 2.06 min, m / z 460 (M + H) +.

Intermediate 9.

3- [6-Bromo-2- (hydroxymethyl) imidazo [1,2-a] pyrazin-3-yl] -3- [5-chloro-2- (difluoromethoxy) phenyl] propanoic acid

Intermediate 8 (225 g, 338 mmol) was stirred in 2M aqueous sodium hydroxide solution (2000 ml) for 60 min until all substance was dissolved. The solution was decanted and acidified to pH = 6 with concentrated aqueous HCl solution (434 g, 4400 mmol, 361 ml, 37%). The solution was neutralized by adding solid NaHCO ₃ (until gas evolution ceased) and extracted twice with EtOAc (1 L). The aqueous layer was re-acidified to pH = 6 and additionally extracted with 2x1000 ml EtOAc, the organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo, evaporated with DCM to give the title compound as a yellow / brown solid (169 g) ... The solid was triturated with diisopropyl ether to give the title compound as a yellow solid (125 g, 77%).

LCMS, Method 3, VV 1.99 min, m / z 478 (M + H) +.

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Intermediate 10.

6-Bromo-3- [1- [5-chloro-2- (difluoromethoxy) phenyl] -3-hydroxy-3-oxopropyl] imidazo [1,2-a] pyrazine-2carboxylic acid

Intermediate 9 (125 g, 262 mmol) was suspended in acetonitrile (1 L) and water (9.45 g, 524 mmol, 9.45 ml). The mixture was cooled to 0 ° C then iodic acid (239 g, 1049 mmol) and chromium trioxide (0.524 g, 5.24 mmol) were added in one portion. The mixture was stirred at 0 ° C for 15 min, then it was allowed to warm to room temperature. The mixture was heated to 45 ° C and stirred for 2.5 h. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was subjected to distribution between water (1 L) and Et ₂ O (750 ml). The layers were separated and the aqueous phase was extracted with Et ₂ O (750 ml). The combined organic layers were washed with brine, dried over (Na ₂ SO ₄ ), filtered and evaporated to dryness to give 124 g of a brown solid.

The solid was triturated with EtOAc to give the title compound as a white solid (72 g).

LCMS, Method 3, VV 1.90 min, m / z 492 (M + H) +.

Intermediate 11.

Methyl 6-bromo-3- [1- [5-chloro-2- (difluoromethoxy) phenyl] -3-methoxy-3-oxopropyl] imidazo [1,2-a] pyrazine-2-carboxylate

Iodomethane (41.7 g, 293 mmol, 18.35 ml) was added with stirring to a mixture of intermediate 10 (72 g, 147 mmol) and potassium carbonate (60.8 g, 440 mmol) in MX-dimethidformamide (500 ml) ... After 2.5 h, additional potassium carbonate (15.21 g, 110 mmol) and iodomethane (10.41 g, 73.4 mmol, 4.59 mL) were added. The reaction mixture was poured into water (2.5 L) and a white suspension was obtained. The mixture was stirred for 30 minutes, then filtered. The filter cake was washed with water and dried to give the title compound (70.6 g) as a white solid.

LCMS, Method 3, VV 2.10 min, m / z 520 (M + H) ⁺ .

Intermediate 12.

Methyl 3-bromo-6- [5-chloro-2- (difluoromethoxy) phenyl] -8-oxo-7,8-dihydro-6H-cyclopenta [4,5] imidazo [1,2-a] pyrazine-7 -carboxylate

Intermediate 11 (17 g, 32.8 mmol) was suspended in toluene (250 ml) and cooled to 0 ° C. Sodium tert-butoxide (7.87 g, 82 mmol) was added in one portion. The mixture turned dark green and stirring was continued at 0 ° C. After 90 min, saturated aqueous NH ₄ Cl solution (400 ml) was added and the mixture was vigorously stirred. The mixture was extracted with EtOAc (x3) and the combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness to give a crude solid. The solid was triturated with a 1: 1 mixture of Et ₂ O and iPr ₂ O to give a red solid. Additional material can be recovered from the mother liquors by silica column chromatography (40% EtOAc in heptane) to provide the title compound as a red / brown solid (5.5 g).

LCMS, Method 3, RT 2.06 min, m / z 488 (M + H) ⁺ .

Intermediate 13.

3-Bromo-6- [5-chloro-2- (difluoromethoxy) phenyl] -6,7-dihydro-8H-cyclopenta [4,5] imidazo [1,2-a] pyrazin8-one

Intermediate 12 (1 g, 2.06 mmol) was dissolved in DMSO (20 ml) then sodium chloride (0.132 g, 2.26 mmol) and water (0.06 ml) were added. The mixture was stirred at 100 ° C until LCMS was

- 23 036289 indicated the completion of the reaction. The reaction mixture was cooled to room temperature and poured into water (400 ml). The mixture was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and the volatiles removed in vacuo to give the title compound as an off-white solid.

LCMS, Method 3, RT 2.02 min, m / z 428 (M + H) ⁺ .

Intermediates 14 and 15.

(6R, 8R) -2-Bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4b] pyrazin-6-ol and ^^) - 2-bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazine-6- ol

Intermediate 13 (410 mg, 0.96 mmol) was dissolved in THF (15 ml) under argon. After cooling to -78 ° C with stirring, L-selectride (956 μl, 1 M solution in THF) was added dropwise. After 30 min, additional L-selectride (23 μl) was added. After 2.5 h, methanol (2.5 ml) was added followed by 1N hydrochloric acid. sodium hydroxide solution (2.5 ml). After warming to room temperature, the aqueous phase was extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (24 g SiO ₂ , DCM / EtOH, 100/0 to 90/10 in 65 min) to give the title compounds as a racemic mixture (209 mg, 51%).

¹ H NMR (400 MHz, DMSO-de) δ 8.93 (d, 1H), 8.31 (d, 1H), 7.42 (dd, 1H), 7.33 (t, 1H), 7, 30 (d, 1H), 6.95 (d, 1H), 5.72 (d, 1H), 5.14 (ddd, 1H), 4.75 (dd, 1H), 3.38-3.49 (m, 1H), 2.10 (dt, 1H). LCMS-M2 (ER +): 1.68 min, 430.0 / 432.0 (M + H) ⁺ .

Intermediates 16 and 17.

2 - [[(6R, 8R) -2-Bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b ] pyrazin-6-yl] oxy] acetonitrile and 2 - [[^^) - 2-bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetonitrile

Sodium hydride (22 mg, 60%) was added to a solution of intermediate products 14 and 15 (105 mg, 240 μmol) in THF (5 ml) with stirring at 0 ° C. After 1 h, bromoacetonitrile (70 μL, 980 μmol) was added dropwise. The ice bath was removed and the reaction mixture was kept overnight. To complete the reaction, the mixture was recooled to 0 ° C and treated with additional sodium hydride (22 mg, 60%). The ice bath was then removed and water was added after 2 hours. The mixture was extracted with EtOAc (3x) and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (4 g SiO ₂ , DCM / EtOH, 100/0 to 90/10 in 65 min) and the isolated product was lyophilized from water / MeCN to give the title compounds as a racemic mixture (71 mg, 62 %).

1H NMR (400 MHz, DMSO-de) δ 9.01 (d, 1H), 8.46 (d, 1H), 7.43 (dd, 1H), 7.31 (t, 1H), 7.30 (d, 1H), 6.84 (d, 1H), 5.75 (s, 1H), 5.15 (dd, 1H), 4.82 (dd, 1H), 4.63-4.75 ( m, 2H), 3.48-3.58 (m, 1H), 2.26 (dt, 1H). LCMSM2 (ER +): 1.83 min, 469.0 / 471.0 (M + H) ⁺ .

Intermediates 18 and 19.

2- [[(6R, 8R) -2-Bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b ] pyrazin-6-yl] oxy] acetamide and 2 - [[^^) - 2-bromo-8- [5-chloro-2- (difluoromethoxy) phenyl] -7,8-dihydro-6H-cyclopenta [1, 2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide

A solution of HBr in acetic acid (1.5 ml, 45 wt%) was added to a solution of intermediate products 16 and 17 (81 mg, 170 μmol) with stirring. After 1 hour, saturated sodium bicarbonate solution was added to neutralize the reaction mixture. After extraction with DCM, the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (4 g SiO ₂ , DCM / EtOH, 100/0 to 90/10 in 65 min) to give the title compounds as a racemic mixture (46 mg, 55%).

1H NMR (400 MHz, DMSO-de) δ 8.98 (d, 1H), 8.39 (d, 1H), 7.42 (dd, 1H), 7.32 (t, 1H), 7.30 (d, 1H), 7.27

- 24 036289 (br s, 1H), 7.09 (br s, 1H), 6.94 (d, 1H), 5.05 (dd, 1H), 4.79 (dd, 1H), 4.09 -4.18 (m, 2H), 3.42-3.53 (m, 1H), 2.34 (dt, 1H). LCMS-M2 (ER +): 1.65 min, 487.0 / 489.0 (M + H) ⁺ .

Example 1. 1- [2- (Difluoromethoxy) phenyl] -8- (6-methoxypyridin-3-yl) -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1, 2-a] pyrazine

To a solution of intermediate 4 (0.22 g, 0.63 mmol) in 1,4-dioxane / water (4.5 / 0.5 ml) was added K ₃ PO ₄ (0.27 g, 1.25 mmol ), (6-methoxy-3-pyridyl) boronic acid (0.14 g, 0.94 mmol) and Pd ₂ (dba) ₃ (0.0057 g, 0.0063 mmol, 0.01 eq.) And the reaction the mixture was heated at 85 ° C for 5 h. The reaction mixture was cooled and treated with water (10 ml), extracted with EtOAc (20 ml), the organics were washed with brine (20 ml), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , 0-3% MeOH / DCM (NH 4 OH 10%)) to give the title compound as an orange solid (75 mg, 28%). LCMS (ER +): VV 1.45 min, 425.0 (M + H) ⁺ .

Example 2. 1- [2- (Difluoromethoxy) phenyl] -8- [2- (morpholin-4-yl) pyrimidin-5-yl] -3,4-dihydro-1Hpyrano [4 ', 3': 4.5 ] imidazo [1,2-a] pyrazine

The title compound was prepared from intermediate 4 and 2-morpholinopyrimidine-5ylboronic acid in a manner analogous to that described for the preparation of the compound of Example 1.

LCMS (ER +): VV 1.41 min, 481.0 (M + H) +.

Example 3. 5- {1- [2- (Difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazin8-yl} pyridine -2 (1 H) -one

To a solution of the compound of Example 1 (0.07 g, 0.17 mmol) in 1,4-dioxane (3 ml) was added HBr (0.15 ml, 0.6 mmol, 48% aqueous solution). The reaction mixture was heated by microwave irradiation at 125 ° C for 0.3 h. Then the reaction mixture was transferred into EtOAc, washed with saturated aqueous NaHCO ₃ solution. The organic phase was dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified using preparative HPLC.

1H NMR (400 MHz, CDCl ₃ ) δ: 9.03 (d, 1H, J 0.6 Hz), 7.94 (dd, J 1.5, 0.7 Hz, 1H), 7.59 (m , 1H), 7.47 (m, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.05 (m, 1H), 6.62 (m, 2H), 6 , 39 (d, J 0.5 Hz, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 3.26 (m, 1H), 3.08 (m, 1H). LCMS (ER +): RB 1.21 min, 411.0 (M + H) ⁺ .

Examples 4 and 5.

Enantiomer 1: (IS or R) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2- a] pyrazine; enantiomer 2: (1R or S) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1Hpyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine

The desired compounds were isolated by purification of 60 mg of intermediate 4 under the conditions of NLC (supercritical liquid chromatography) using WhelkO-01 (R, R) (50x227 mmhmm, flow rate: 360 ml / min, 25 ° C, CO ₂ + 20% i-PrOH, 5 ml of solution was injected at a concentration of 20 g / L).

The first eluted enantiomer (RT 7.31 min) was collected and the fractions were evaporated to give (enantiomer 1) ((1S or R) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro- 1H-pyrano [4 ', 3': 4.5] imidazo [1,2-a] pyrazine (16 mg, 27%, the compound of Example 4) LCMS (ER +): VA 1.40 min, 396.0 / 398.0 (M + H) ⁺ .

The enantiomer eluting the second (VV 8.99 min) was collected and the fractions were evaporated to obtain (enantiomer 2) (1R or S) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H -pyrano [4 ', 3': 4.5] im-25 036289 dazo [1,2-a] pyrazine (13 mg, 22%, the compound of example 5). LCMS (ER +): VA 1.40 min, 396.0 / 398.0 (M + H) ⁺ .

Examples 6 and 7. Enantiomer 1: (1S or R) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1Hpyrano [4 ', 3': 4,5] imidazo [1 , 2-a] pyrazine; enantiomer 2: (1R or S) -8-bromo-1- [2- (difluoromethoxy) phenyl] 3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a ] pyrazine

The desired compounds were isolated by purifying 60 mg of intermediate 4 under NLC conditions using WhelkO-01 (R, R) (50x227 mmhmm, flow rate: 360 ml / min, 25 ° C, CO ₂ + 20% i-PrOH, injected 5 ml of solution at a concentration of 20 g / l).

The first eluted enantiomer (RT 7.31 min) was collected and the fractions were evaporated to give (enantiomer 1) ((1S or R) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro- 1H-pyrano [4 ', 3': 4.5] imidazo [1,2-a] pyrazine (16 mg, 27%, the compound of Example 4) LCMS (ER +): VA 1.40 min, 396.0 / 398.0 (M + H) +.

The enantiomer eluting the second (VV 8.99 min) was collected and the fractions were evaporated to obtain (enantiomer 2) (1R or S) -8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H -pyrano [4 ', 3': 4.5] imidazo [1,2-a] pyrazine (13 mg, 22%, the compound of example 5). LCMS (ER +): VA 1.40 min, 396.0 / 398.0 (M + H) ⁺ .

Examples 8 and 9. Enantiomer 1: (6R, 8R) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1methylethyl) -3-pyridyl] -7.8 -dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-ol; enantiomer 2:

(6S, 8S) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1 -methylethyl) -3-pyridyl] -7,8-dihydro-6Нcyclopenta [1 , 2] imidazo [3,4-b] pyrazin-6-ol

To a solution of intermediate products 14 and 15 (85 mg, 200 μmol) in a DME / water mixture (4/1 ml) was added Na ₂ CO ₃ (84 mg, 790 μmol), 2- (5- (4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2yl) propan-2-ol (109 mg, 390 μmol) and complex of 1,1'-bis (diphenylphosphino) ferrocenepalladium (P) dichloride with dichloromethane (32 mg, 40 μmol) and the reaction mixture was heated in a microwave oven at 100 ° C for 15 min. The reaction mixture was cooled, treated with water and extracted with EtOAc (3x). The combined organics were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (4 g SiO ₂ , DCM / EtOH, 100/0 to 90/10 in 65 min) to give the title compounds as a racemic mixture (93 mg), which required further purification. After reverse phase column chromatography (column: Agilent Prep-C18 (21.5x250 mm), 10 μm, flow rate: 40 ml / min; gradient mode: MeCN / water, 10/90 (0 min), 90/10 ( 12.5 min), 90/10 (15 min)), 55 mg of racemate was obtained.

The desired compounds were isolated by separation of the racemate on a Chiralpak IC column [(250x30 mm x mm), 5 μm, flow rate: 30 ml / min, RT, a mixture of heptane ^ 10 ^ MeOH of the composition 5: 1: 1 + 0.02% TFA (trifluoroacetic acid ].

The first eluting enantiomer (VU 15.7 min) was collected and the combined fractions were evaporated and lyophilized from MeCN / water. The residue was treated with a mixture of water, saturated sodium bicarbonate solution and DCM. After extraction of the aqueous solution with DCM (3x), the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. After additional reverse phase column chromatography [column: Agilent Prep-C18 (21.5x250 mm), 10 μm, flow rate: 40 ml / min; gradient mode: MeCN / water, 10/90 (0 min), 90/10 (12.5 min), 90/10 (15 min)] and lyophilization from a water / MeCN mixture obtained enantiomer 1, (6R, 8R) - 8- [5-chloro-2 (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1 -methylethyl) -3-pyridyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [ 3,4-b] pyrazin-6-ol (17 mg, 18%, the compound of example 8).

¹ H NMR (DMSO-66) δ: 9.19 (d, 1H), 8.99 (d, 1H), 8.57 (d, 1H), 8.26 (dd, 1H), 7.74 ( d, 1H), 7.41 (dd, 1H), 7.40 (t, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 5.70 (br d, 1H) , 5.25 (s, 1H), 5.13-5.19 (m, 1H), 4.82 (dd, 1H), 3.43-3.53 (m, 1H), 2.14 (dt , 1H), 1.45 (s, 6H). LCMS-M2 (ER +): VV 1.50 min, 487.2 (M + H) ⁺ .

The second eluting enantiomer (RT 22.7 min) was collected and worked up as described for enantiomer 1 to give enantiomer 2, ^^) - 8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [ 6- (1-hydroxy1-methylethyl) -3-pyridyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-ol (19 mg, 20%, compound Example 9).

1H NMR (DMSO-de) δ: 9.19 (d, 1H), 8.99 (d, 1H), 8.57 (d, 1H), 8.26 (dd, 1H), 7.74 (d , 1H), 7.41 (dd, 1H), 7.40 (t, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 5.70 (d, 1H), 5 , 26 (s, 1H), 5.13-5.19 (m, 1H), 4.82 (dd, 1H), 3.43-3.52 (m, 1H), 2.15 (dt, 1H ), 1.45 (s, 6H). LCMS-M2 (ER +): VV 1.50 min, 487.2 (M + H) +.

- 26 036289

Examples 10 and 11.

Enantiomer 1: 2 - [[(6K., 8K) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3pyridyl] -7.8 -dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide; enantiomer 2: 2 [[^^) - 8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro -6Ncyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide

F

To a solution of intermediate products 18 and 19 (44 mg, 90 μmol) in a DME / water mixture (4/1 ml), Na ₂ CO ₃ (39 mg, 360 μmol), 2- (5- (4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2yl) propan-2-ol (50 mg, 180 μmol) and the complex of 1,1'-bis (diphenylphosphino) ferrocenepalladium (P) dichloride with dichloromethane (15 mg, 20 μmol) and the reaction mixture was heated in a microwave oven at 100 ° C for 15 min. The reaction mixture was cooled, treated with water and extracted with EtOAc (3x). The combined organics were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (4 g SiO ₂ , DCM / EtOH, 100/0 to 85/15 in 65 min) to give the title compounds as a racemic mixture (48 mg).

The desired compounds were isolated by separation of the racemate on a Chiralpak IF column [(250x30 mmхmm), 5 μm, flow rate: 30 ml / min, RT, mixture ιόιπήιι: 1 · 1ΟΙ 1: МеО11 composition 2: 1: 1 + 0.1% diethylamine ].

The first eluting enantiomer (RT 13.4 min) was collected and the combined fractions were evaporated and lyophilized from MeCN / water to obtain enantiomer 1, (6K, 8K) -8- [5-chloro-2 (difluoromethoxy) phenyl] -2 - [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-ol (16 mg, 32%, compound of example 10).

1H NMR (DMSO-de) δ: 9.24 (d, 1H), 9.01 (d, 1H), 8.65 (d, 1H), 8.28 (dd, 1H), 7.74 (d , 1H), 7.42 (dd, 1H), 7.38 (t, 1H), 7.32 (d, 1H), 7.28 (br s, 1H), 7.10 (br s, 1H) , 6.94 (d, 1H), 5.26 (s, 1H), 5.07 (dd, 1H), 4.86 (dd, 1H), 4.16 (s, 2H), 3.48- 3.58 (m, 1H), 2.38 (dt, 1H), 1.45 (s, 6H). LCMS-M2 (ER +): VV 1.48 min, 544.2 (M + H) ⁺ .

The enantiomer eluted second (RT 16.4 min) was collected and the fractions were evaporated and lyophilized from MeCN / water to obtain the enantiomer 2, 2 - [[^^) - 8- [5-chloro-2- (difluoromethoxy) phenyl] -2 [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide (16 mg, 33%, the compound of example 11).

1H NMR (DMSO-de) δ: 9.24 (d, 1H), 9.01 (d, 1H), 8.65 (d, 1H), 8.28 (dd, 1H), 7.74 (d , 1H), 7.42 (dd, 1H), 7.38 (t, 1H), 7.32 (d, 1H), 7.28 (br s, 1H), 7.10 (br s, 1H) , 6.94 (d, 1H), 5.26 (s, 1H), 5.07 (dd, 1H), 4.86 (dd, 1H), 4.16 (s, 2H), 3.48- 3.58 (m, 1H), 2.32-2.41 (dt, 1H), 1.45 (s, 6H). LCMS-M2 (ER +): VV 1.48 min, 544.2 (M + H) +.

Claims (12)

CLAIM 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof R ³ Y (I) in which n denotes an integer equal to 0 or 1; Y is phenyl, which may optionally have one or more substituents selected from halogen and difluoromethoxy; X represents oxygen or a linear or branched _C1-C4 alkylene chain; R ¹ denotes halogen or heteroaryl, which may optionally contain one or more substituents selected from hydroxy, hydroxy (C1-Cb) alkyl and CgCb-alkoxy; R ² and R ³ independently represent hydrogen; R ⁴ is hydrogen; R ^5a is hydrogen, hydroxy or —OR ^a ; R ^5b is hydrogen; R ^a is a C1-Sa-alkyl which may optionally contain one or more substituents selected from _C1-C6 alkoxy, oxo, and aminocarbonyl; and - 27 036289 where heteroaryl means monovalent aromatic groups containing at least 5 atoms formed from one ring or a plurality of fused rings in which one or more carbon atoms have been replaced by one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. 2. A compound according to claim 1 of formula (IIA) or a pharmaceutically acceptable salt thereof (HA) in which X, Y, R ¹ , R ^5a and R ^5b are as defined in claim 1. 3. A compound according to claim 2 of formula (IIA-AB) or a pharmaceutically acceptable salt thereof (PA-AB) in which V is CR ¹¹ or N; R ⁶ is halogen or difluoromethoxy; R ⁷ is hydrogen or halogen; R ⁸ is hydroxy, C ₁ -C ₆ -α alkoxy or hydroxy (C ₁ -C ₆ ) alkyl; R ⁹ , R ¹⁰ and R ^{11 are} independently hydrogen and X, R ^a , R ^5a and R ^5b are as defined in claim 1. 4. The compound of claim 2, wherein X is oxygen. 5. A compound according to claim 1 of formula (IIB) or a pharmaceutically acceptable salt thereof γ (HB) in which X, Y, R ¹ , R ^5a and R ^5b are as defined in claim 1. 6. A compound according to claim 5 of formula (IIB-AB) or a pharmaceutically acceptable salt thereof (PV-AB) in which V, X, R ^5a , R ^5b , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are as defined above in paragraph 3. 7. A compound according to claim 5, wherein X is a methylene group. 8. The compound according to claim 1, selected from the group consisting of 1- [2- (difluoromethoxy) phenyl] -8- (6-methoxypyridin-3-yl) -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a ] pyrazine; 1- [2- (difluoromethoxy) phenyl] -8- [2- (morpholin-4-yl) pyrimidin-5-yl] -3,4-dihydro-1H-pyrano [4 ', 3': 4.5] imidazo [1,2-a] pyrazine; 5- {1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-1H-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazin-8-yl} pyridine- 2 (1H) -one; (^) - 8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-III-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine; (^) - 8-bromo-1- [2- (difluoromethoxy) phenyl] -3,4-dihydro-III-pyrano [4 ', 3': 4,5] imidazo [1,2-a] pyrazine; (6R, 8R) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro-6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-ol; (6S, 8S) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro6H-cyclopenta [1 , 2] imidazo [3,4-b] pyrazin-6-ol; 2- [[(6R, 8R) -8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro -6H-cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide and 2 - [[^^) - 8- [5-chloro-2- (difluoromethoxy) phenyl] -2- [6- (1-hydroxy-1-methylethyl) -3-pyridyl] -7,8-dihydro-6H -cyclopenta [1,2] imidazo [3,4-b] pyrazin-6-yl] oxy] acetamide. - 28 036289 9. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of a disorder for which administration of a TNFa inhibitor is indicated. 10. The use of a compound of formula (I) according to claim 9 for the treatment and / or prevention of an inflammatory or autoimmune disorder. 11. Use of a compound of formula (I) according to claim 10 for the treatment of rheumatoid arthritis or Crohn's disease. 12. A pharmaceutical composition that inhibits the activity of TNFa, containing a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.